Tissue remodeling is a distinct feature of human endometrium in the secretory phase leading to a tissue ready for implantation during the """"""""receptive phase"""""""" of the cycle. A discrete dissolution of extracellular matrix by a host of enzymes called matrix metalloproteases (MMP) is a requirement for a successful implantation. In the absence of implantation, human endometrium loses its receptive state in the premenstrual period and subsequently undergoes a qeneralized tissue breakdown during menstruation by MMPs. Factors that lead to this non-receptive state, cause perturbation of embryo implantation and ultimately lead to tissue shedding have not yet been identified. This gap in our knowledge is clinically significant because, by knowing what fosters localized dissolution of tissue during implantation and generalized tissue breakdown during menstruation, effective treatment for infertility and controlling abortion could be developed. TGF-beta is an integral component of implantation processes which controls both the expression of collagen mRNA as well as breakdown of extracellular matrix. The PIs have recently shown that lefty inhibits TGF-beta signaling and causes implantation failure in pregnant mice. The long-range goal is to understand how lefty prevents implantation. The objective of this application is to determine the extent of involvement of lefty in the control of implantation. The central hypothesis of this application is that lefty, by inhibiting the TGF-beta signaling, prevents collagen deposition and causes collagenolysis. The hypothesis has been formulated on the basis of strong published and preliminary findings, which show that lefty inhibits TGF-beta signaling, reduces collagen mRNA synthesis and increases collagenolysis. Moreover, lefty is expressed in endometrium at a low level during the receptive phase but is overexpressed during the non-receptive phase of menstrual cycle in normal fertile women. In some infertile women, lefty is overexpressed during the receptive phase of the cycle. Induction of such overexpression causes implantation failure in pregnant mice. The rationale for the proposed research is that, once it is known how lefty regulates endometrial remodeling, then new and innovative approaches can be developed for prevention or treatment of human infertility and abortion. The PIs plan to test their central hypothesis and accomplish the objectives of this application by pursuing the following three specific aims: to assess the extent that lefty regulates (1) deposition of collagen, (2) collagenolytic activity, and (3) implantation. The proposed work capitalizes on a new and viable means for regulating the endometrial receptivity and tissue breakdown. It is expected that the proposed approaches will identify lefty as a key factor essential to regulation of endometrial receptivity for embryo implantation. These results are expected to demonstrate the feasibility of using lefty protein as a target in therapeutic interventions for infertility and related disorders and abortion.
